The bioaccumulation of halogenated organic compounds (HOCs) in the marine food web provides a direct route for human exposure to several classes of persistent organic pollutants. Natural polybrominated organic compounds such as polybrominated diphenyl ethers, polybrominated dibenzodioxins and polybrominated bipyrroles are collectively proposed to be synthesized by marine organisms such as cyanobacteria and red algae involving unknown metabolic pathways harboring yet to be discovered halogenating enzymes. The goals of this project are to provide a genetic and biochemical foundation for the microbial biosynthesis of HOCs in the marine environment. Our research strategy includes a comprehensive genetic, biochemical, and enzyme structure-based analysis of polybrominated metabolite biosynthesis in two model marine bacterial groups, Pseudoalteromonas and Streptomyces, as well as other HOC producing strains discovered in the course of the research. We will provide a direct interrogation of natural maririe samples enriched in HOCs to identify and characterize the prevalence of these biosynthetic pathways in the marine environment. The proposed work will be undertaken jointly by the laboratories of Allen and Moore at Scripps who have a proven track record of collaboration and joint student mentorship. The success of this Project is based on biochemists, microbiologists, structural biologists and genome scientists working together; thus we have enlisted the help of Moore's long-standing collaborator Prof. Joseph Noel (Salk Institute for Biological Studies, La Jolla) to join the Project through a sub-contract to assist in the protein crystallography of brominating enzymes in order to provide a detailed understanding of the structural basis behind enzymatic bromination. Collectively, this project will deliver new molecular-based insight into organohalogen biosynthesis that will be united with other Center investigations to explore the diversity and ecology of these compounds and their impacts on oceans and human health. 1